Genistein effects on stromal cells determines epithelial proliferation in endometrial co-cultures |
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Authors: | Sampey Brante P Lewis Terrence D Barbier Claire S Makowski Liza Kaufman David G |
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Affiliation: | aDepartment of Pathology and Laboratory Medicine, 620 Brinkhous-Bullitt Building, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599–7525, USA;bDepartment of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599–7525, USA;cLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599–7525, USA |
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Abstract: | BackgroundEstrogen is the leading etiologic factor for endometrial cancer. Estrogen-induced proliferation of endometrial epithelial cells normally requires paracrine growth factors produced by stromal cells. Epidemiologic evidence indicates that dietary soy prevents endometrial cancer, and implicates the phytoestrogen genistein in this effect. However, results from previous studies are conflicting regarding the effects of genistein on hormone responsive cancers.MethodsThe effects of estrogen and genistein on proliferation of Ishikawa (IK) endometrial adenocarcinoma cells were examined in co-cultures of IK cells with endometrial stromal cells, recapitulating the heterotypic cell-to-cell interactions observed in vivo. The roles of estrogen receptor (ER)α and ERβ were evaluated using ERα and ERβ specific agonists. ER activation and cell proliferation in the IK epithelial cells were determined by alkaline phosphatase assay and Coulter counter enumeration, respectively.ResultsBoth estrogen and genistein increased estrogen receptor-induced gene activity in IK cells over a range of concentrations. Estrogen alone but not genistein increased IK proliferation in co-cultures. When primed by estrogen treatment, increasing concentrations of genistein produced a biphasic effect on IK proliferation: nM concentrations inhibited estrogen-induced proliferation while μM concentrations increased proliferation. Studies with an ERβ-specific agonist produced similar results. Genistein did not influence the effects of estrogen on IK proliferation in monoculture.ConclusionsOur study indicates that nutritionally relevant concentrations (nM) of genistein inhibit the proliferative effects of estrogen on endometrial adenocarcinoma cells presumably through activation of stromal cell ERβ. We believe that sub-micromolar concentrations of genistein may represent a novel adjuvant for endometrial cancer treatment and prevention. |
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Keywords: | Genistein Endometrium Co-culture Ishikawa Stromal cell Estrogen receptor |
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